Compositions comprising an inhibitor of lysine specific demethylase-1

Patent metadata

Field	Value
Publication number	US-9828358-B2
Application number	US-201615344426-A
Country	US
Kind code	B2
Filing date	Nov 4, 2016
Priority date	Nov 5, 2015
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

Described herein are amorphous and crystalline forms of pharmaceutically acceptable salts of the lysine specific demethylase-1 inhibitor 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-4-yl]-2-fluorobenzonitrile. Also described are pharmaceutical compositions suitable for administration to a mammal that include the lysine specific demethylase-1 inhibitor, and methods of using the lysine specific demethylase-1 inhibitor for treating diseases or conditions that are associated with lysine specific demethylase-1 activity.

First claim

What is claimed is:

1. A pharmaceutically acceptable salt of 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-4-yl]-2-fluorobenzonitrile, wherein the pharmaceutically acceptable salt is in crystalline form.

2. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is a p-toluene sulfonic acid salt, sulfuric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt, phosphoric acid salt, or benzoic acid salt.

3. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is a benzenesulfonic acid salt.

4. A crystalline form of 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-4-yl]-2-fluorobenzonitrile besylate salt, designated Form 1, wherein the crystalline form that exhibits the following characteristics:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1 ;
(b) an XRPD pattern with characteristic peaks at 4.9° 2-Theta, 9.7° 2-Theta, 13.4° 2-Theta, 18.0° 2-Theta, and 18.5° 2-Theta;
(c) a DSC thermogram with an endotherm having an onset temperature at about 317° C.;
(d) a DSC thermogram substantially similar to the one set forth in FIG. 2 ; or
(e) combinations thereof.

5. The crystalline form of claim 4 , wherein the crystalline form exhibits a characteristic XRPD pattern substantially the same as shown in FIG. 1 .

6. The crystalline form of claim 4 , wherein the crystalline form exhibits a characteristic XRPD pattern with characteristic peaks at 4.9° 2-Theta, 9.7° 2-Theta, 13.4° 2-Theta, 18.0° 2-Theta, and 18.5° 2-Theta.

7. The crystalline form of claim 4 , wherein the crystalline form exhibits substantially the same characteristic XRPD pattern after storage at 40° C. and 75% RH for at least a week.

8. The crystalline form of claim 4 , wherein the crystalline form exhibits substantially the same characteristic XRPD pattern after storage at 25° C. and 96% RH for at least a week.

9. The crystalline form of claim 4 , wherein the crystalline form exhibits a DSC thermogram with an endotherm having an onset temperature at about 317° C.

10. A composition comprising a crystalline form of claim 1 .

11. A pharmaceutical composition comprising the crystalline form of claim 1 , and at least one pharmaceutically acceptable carrier, diluent, or excipient.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is in an oral dosage form.

13. The pharmaceutical composition of claim 12 , wherein the oral dosage form is a tablet, capsule or pill.

14. 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-4-yl]-2-fluorobenzonitrile besylate salt that is in amorphous form.

15. A pharmaceutical composition comprising amorphous 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-4-yl]-2-fluorobenzonitrile besylate salt, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

16. The pharmaceutical composition of claim 15 , wherein the pharmaceutical composition is an oral dosage form.

17. The pharmaceutical composition of claim 16 , wherein the oral dosage form is a tablet, capsule, or pill.

18. A pharmaceutical composition comprising the crystalline form of claim 4 and at least one pharmaceutically acceptable carrier, diluent, or excipient.

19. A method of treating acute myeloid leukemia, breast or prostate cancer in a mammal comprising administering to the mammal the pharmaceutical composition of claim 18 .

20. A method of treating acute myeloid leukemia, breast or prostate cancer in a mammal comprising administering to the mammal the pharmaceutical composition of claim 15 .

Assignees

• Celgene Quanticel Res Inc

Inventors

• Chen Young K
• Kanouni Toufike
• Kaldor Stephen W
• Stafford Jeffrey Alan
• Veal James Marvin
• Tavares-Greco Paula Alessandra
• Kreilein Matthew Michael

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• C07D239/36

  as doubly bound oxygen atom or as unsubstituted hydroxy radical · CPC title